On December 19, 2016 Clovis Oncology, Inc. (NASDAQ:CLVS) reported that the U.S. Food and Drug Administration (FDA) has approved Rubraca (rucaparib) tablets as monotherapy for the treatment of patients with deleterious BRCA mutation (germline and/or somatic) associated advanced ovarian cancer, who have been treated with two or more chemotherapies, and selected for therapy based on an FDA-approved companion diagnostic for Rubraca (Press release, Clovis Oncology, DEC 19, 2016, View Source [SID1234517133]). Rubraca’s indication is approved under the FDA’s accelerated approval program, and is based on objective response rate and duration of response results from two multicenter, single-arm, open-label clinical trials, Study 10 and ARIEL2 Parts 1 and 2. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. The ARIEL3 maintenance confirmatory study has completed enrollment and the ARIEL4 treatment confirmatory study is open for enrollment. Warning and precautions include Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML). Please see additional warnings and precautions and Select Important Safety Information below.

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"Recurrent ovarian cancer remains one of the most difficult cancers to treat and for so many years, medical advances in this space have been limited," said Robert L. Coleman, MD, Professor & Deputy Chairman, Vice Chair, Clinical Research, Ann Rife Cox Chair in Gynecology, Department of Gynecologic Oncology and Reproductive Medicine at University of Texas MD Anderson Cancer Center in Houston and one of the Principal Investigators in the ARIEL clinical trial program. "Today’s approval of Rubraca for the treatment of advanced ovarian cancer demonstrates the value of treatment with PARP inhibitors and represents an important advance for women diagnosed with either germline or somatic BRCA-mutated tumors who have been treated with two or more chemotherapies."

"We believe that today’s approval of Rubraca provides an important new therapy for advanced ovarian cancer patients with a germline or somatic mutation of BRCA after two or more chemotherapies," said Patrick J. Mahaffy, CEO and President of Clovis Oncology. "We look forward to launching Rubraca with the support of our established U.S. commercial and medical affairs organizations and bringing this much-needed precision medicine to women with advanced ovarian cancer as quickly as possible."

"NOCC commends Clovis Oncology for its commitment to bringing a new treatment option to women living with ovarian cancer, the deadliest cancer of the female reproductive system. All too often, women are diagnosed when the disease is far advanced, leaving them with few viable treatment options," said David Barley, Chief Executive Officer, National Ovarian Cancer Coalition. "The development and FDA approval of therapies for use in third-line is a promising step forward for the tens of thousands of women who will battle ovarian cancer in their lifetime."

"Ovarian cancer is one of the most difficult cancers to detect. For this reason, most women who develop ovarian cancer are diagnosed with advanced disease," said Sue Friedman, DVM, Executive Director of Facing Our Risk of Cancer Empowered. "There is a tremendous need for new ways to treat women with advanced ovarian cancer and ways to find those women who will respond to therapies such as PARP inhibitors. PARP inhibitors, like Rubraca, represent an exciting advancement for appropriate patients."

The Rubraca NDA filing received Priority Review and was reviewed and approved under FDA’s Accelerated Approval program. These programs allow for earlier approval of drugs that treat serious conditions and that fill an unmet medical need. The application was based on objective response rate and duration of response results from two multicenter, single-arm, open-label clinical trials, Study 1 (Study 10, NCT01482715) and Study 2 (ARIEL2 Parts 1 and 2, NCT01891344), in women with advanced BRCA-mutant ovarian cancer who had progressed after two or more prior chemotherapies. All 106 patients received Rubraca orally 600 mg twice daily as monotherapy until disease progression or unacceptable toxicity. Objective response rate (ORR) and duration of response (DOR) were assessed by the investigator and independent radiology review (IRR) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.

Clovis partnered with Foundation Medicine, Inc. to co-develop a companion diagnostic test, the FDA approved FoundationFocusTM CDxBRCA, to select patients for Rubraca treatment. FoundationFocus CDxBRCA is a tissue-based, genomic assay that detects tumor BRCA1 and BRCA2 mutations (germline and/or somatic) in ovarian cancer.

Efficacy and safety results from the U.S. Prescribing Information are summarized below:

Overall Response and Duration of Response in Patients with BRCA-mutant Ovarian Cancer Who Received 2 or More Chemotherapies in Study 1 and Study 2



Investigator-assessed
N=106
Objective Response Rate (95% CI) 54% (44, 64)
Complete Response 9%
Partial Response 45%
Median DOR in months (95% CI) 9.2 (6.6, 11.6)

Response assessment by IRR was 42% (95% CI: 32, 52), with a median DOR of 6.7 months (95% CI: 5.5, 11.1). Investigator-assessed ORR was 66% (52/79; 95% CI: 54, 76) in platinum-sensitive patients, 25% (5/20; 95% CI: 9, 49) in platinum-resistant patients, and 0% (0/7; 95% CI: 0, 41) in platinum-refractory patients. ORR was similar for patients with a BRCA1 gene mutation or BRCA2 gene mutation.

The overall safety evaluation of Rubraca 600 mg twice daily as monotherapy is based on data from 377 patients with ovarian cancer treated in two open-label, single arm trials. The most common adverse reactions (≥ 20% of patients; Grade 1-4) were nausea, asthenia/fatigue, vomiting, anemia, constipation, dysgeusia, decreased appetite, diarrhea, abdominal pain, thrombocytopenia and dyspnea. The most common laboratory abnormalities (≥ 35% of patients; Grade 1-4) were increase in creatinine, increase in ALT, increase in AST, decrease in hemoglobin, decrease in lymphocytes, increase in cholesterol, decrease in platelets and decrease in absolute neutrophil count.

About Rubraca Connections

Rubraca will be available in the United States immediately. For those who are eligible, Clovis Oncology plans to offer programs through Rubraca Connections to support patients taking Rubraca. More information about Rubraca Connections is available at RubracaConnections.com or by calling 1-844-779-7707 between 8 am and 8 pm Eastern, Monday through Friday.

About RubracaTM (rucaparib)

Rubraca is a PARP inhibitor indicated as monotherapy for the treatment of patients with deleterious BRCA mutation (germline and/or somatic) associated advanced ovarian cancer, who have been treated with two or more chemotherapies, and selected for therapy based on an FDA-approved companion diagnostic for Rubraca. Rubraca’s indication is approved under the FDA’s accelerated approval program based on objective response rate and duration of response, and is based on results from two multicenter, single-arm, open-label clinical trials. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Select Important Safety Information

There are no contraindications with Rubraca.

Myelodysplastic Syndrome (MDS)/Acute Myeloid Leukemia (AML) was reported in 2 of 377 (0.5%) patients with ovarian cancer treated with Rubraca. The duration of Rubraca treatment prior to the diagnosis of MDS/AML was 57 days and 539 days. Both patients received prior treatment with platinum and other DNA damaging agents.

AML was reported in 2 (<1%) patients with ovarian cancer enrolled in ARIEL3, a blinded, randomized trial evaluating Rubraca versus placebo. One case of AML was fatal. The duration of treatment prior to the diagnosis of AML was 107 days and 427 days. Both patients had received prior treatment with platinum and other DNA damaging agents.

Do not start Rubraca until patients have recovered from hematological toxicity caused by previous chemotherapy (≤ Grade 1).

Monitor complete blood count testing at baseline and monthly thereafter. For prolonged hematological toxicities, interrupt Rubraca and monitor blood counts weekly until recovery. If the levels have not recovered to Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confirmed, discontinue Rubraca.

Rubraca can cause fetal harm when administered to pregnant women based on its mechanism of action and findings from animal studies. Apprise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of Rubraca.

Most common adverse reactions (≥ 20%; Grade 1-4) were nausea (77%), asthenia/fatigue (77%), vomiting (46%), anemia (44%), constipation (40%), dysgeusia (39%), decreased appetite (39%), diarrhea (34%), abdominal pain (32%), dyspnea (21%), and thrombocytopenia (21%).

Most common laboratory abnormalities (≥ 35%; Grade 1-4) were increase in creatinine (92%), increase in alanine aminotransferase (ALT) (74%), increase in aspartate aminotransferase (AST) (73%), decrease in hemoglobin (67%), decrease in lymphocytes (45%), increase in cholesterol (40%), decrease in platelets (39%), and decrease in absolute neutrophil count (35%).

Because of the potential for serious adverse reactions in breast-fed infants from Rubraca, advise lactating women not to breastfeed during treatment with Rubraca and for 2 weeks after the final dose.

Please see the U.S. Prescribing Information for full safety and efficacy or visit www.Rubraca.com for more information.

On December 19, 2016 Threshold Pharmaceuticals, Inc. (NASDAQ:THLD), a clinical-stage biopharmaceutical company developing novel therapies for cancer, reported that it has entered into a collaboration with the National Cancer Institute (NCI), part of the National Institutes of Health (NIH), to study TH-3424, the company’s new drug candidate for the treatment of cancer (Press release, Threshold Pharmaceuticals, DEC 19, 2016, View Source [SID1234517126]). The collaboration will explore the effects of TH-3424 against T-cell acute lymphoblastic leukemia (T-ALL) xenograft cell lines with high AKR1C3 expression. The studies will be conducted through the NCI-funded Pediatric Preclinical Testing Consortium (PPTC). Under this collaboration, Threshold will supply TH-3424, and the NCI will fund the studies that will be conducted at the PPTC leukemia research program led by Professor Richard Lock of Children’s Cancer Institute (Sydney, Australia).

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TH-3424 is a novel, small-molecule compound invented at Threshold with potentially broad anticancer properties. TH-3424 is activated by the enzyme AKR1C3, which is over-expressed in a number of different cancers, to release a cytotoxic agent directly to the tumor. Preclinical results showed that TH-3424 is effective in a variety of human xenograft models of cancer, as initially presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in April 2016.

"TH-3424 is designed to be activated by AKR1C3 inside tumor cells and spare healthy tissue," said Barry Selick, Ph.D., CEO of Threshold Pharmaceuticals. "Evaluating this compound in collaboration with the NCI enables us to expand the scope of our investigations to better inform our strategy for potential future clinical studies for this molecule."

About TH-3424
TH-3424 is a small-molecule drug candidate being evaluated for the potential treatment of hepatocellular cancer (HCC), castrate resistant prostate cancer (CRPC), T-cell acute lymphoblastic leukemias (T-ALL), and other cancers expressing high levels of aldo-keto reductase family 1 member C3 (AKR1C3). Tumors overexpressing AKR1C3 can be resistant to radiation therapy and chemotherapy and immunotherapy. TH-3424 is a prodrug that selectively releases a potent DNA cross-linking agent in the presence of AKR1C3. Investigational New Drug (IND)-enabling toxicology studies are being done in collaboration with Ascenta Pharmaceuticals, Ltd.

On December 19, 2016 Kite Pharma, Inc. (Nasdaq:KITE) reported several updates to its broad intellectual property portfolio relating to the use of chimeric antigen receptors (CARs) to harness the power of a patient’s immune cells (Press release, Kite Pharma, DEC 19, 2016, View Source [SID1234517123]). These updates include a recent U.S. Patent and Trademark Office (USPTO) decision concerning one narrow patent related to CAR products containing a pre-specified CD28 costimulatory domain, and a recent favorable result in a challenge at the USPTO to one of Kite’s important CAR-T patents, U.S. Patent Number 6,319,494.

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In August 2015, Kite preemptively filed a petition with the U.S. Patent and Trademark Office (USPTO) to institute an inter partes review (IPR) of U.S. Patent No. 7,446,190 owned by Sloan Kettering Institute for Cancer Research and licensed by Juno Therapeutics, Inc. The IPR was aimed at invalidating the ‘190 patent, which has a narrow scope directed to CAR products containing a pre-specified CD28 costimulatory domain. The USPTO’s recent ruling in this matter did not revoke the patent. However, Kite continues to believe the patent to be invalid and plans to appeal the USPTO decision to the U.S. Court of Appeals for the Federal Circuit. This patent does not have any counterpart patents outside of the United States.

The USPTO’s decision will have no impact on the timing of the rolling submission or review of the Biologics License Application for Kite’s lead product candidate, axicabtagene ciloleucel (KTE-C19), a potentially lifesaving investigational therapy that has demonstrated the most advanced utilization of the CD28 costimulatory domain in a CAR-T therapy to date. Axicabtagene ciloleucel is currently being developed for the treatment of CD19 positive B cell malignancies, including non-Hodgkin lymphoma and acute lymphoblastic leukemia.

Separately, Kite recently defeated an anonymous challenge filed against U.S. Patent Number 6,319,494, developed by Kite’s Senior Vice President of Discovery Research, Margo Roberts, Ph.D. and colleagues. This patent, which covers methods for treating a viral disease or malignancy using modified T cells that contain single-chain variable fragment (scFv) binding elements and other key CAR-T features, impacts multiple competitor CAR-T cell product candidates under development.

In addition to the Roberts patent, Kite’s growing intellectual property portfolio encompasses more than 150 patent assets including an exclusive license to U.S. Patent No. 7,741,465, a leading and widely significant patent directed to CAR-T constructs, developed by Dr. Zelig Eshhar and colleagues. This patent, currently under reexam by the USPTO, potentially impacts CAR-T products under development by multiple Kite competitors.

On December 19, 2016 Juno Therapeutics, Inc. (NASDAQ: JUNO), a biopharmaceutical company developing innovative cellular immunotherapies for the treatment of cancer, reported that it has defeated an attempt to invalidate a patent exclusively licensed by Juno that covers, among other things, a chimeric antigen receptor (CAR) T cell used for the treatment of B-cell malignancies, and that it is suing Kite Pharma, Inc., seeking a declaratory judgment that Kite’s lead product candidate, KTE-C19, will infringe the patent when commercially produced(Press release, Juno, DEC 19, 2016, View Source [SID1234517122]).

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In August 2015, Kite Pharma, Inc. filed an inter partes review in the U.S. Patent & Trademark Office in an attempt to invalidate U.S. Patent No. 7,446,190 by challenging all of its claims. Juno exclusively licenses the ’190 patent, titled "Nucleic Acids Encoding Chimeric T Cell Receptors," from Sloan Kettering Institute for Cancer Research, an affiliate of Memorial Sloan Kettering Cancer Center. The patent covers, among other things, a construct for a CD-19 targeted CAR T cell treatment that employs a CD28 costimulatory domain.

The U.S. Patent & Trademark Office instituted a review of the patent and on December 16, 2016 issued a final written decision upholding all the claims of the patent.

"We are obviously pleased by the USPTO’s decision to uphold the patent," said Bernard J. "Barney" Cassidy, General Counsel of Juno Therapeutics. "Our efforts to amicably and reasonably resolve the dispute Kite initiated have been thwarted and today we are taking the next step towards fully resolving matters. Importantly, our filing will not prevent continued patient access while the legal dispute continues."

The lawsuit is being filed in the U.S. District Court for the District of Delaware. Juno and the Sloan Kettering Institute are represented by Irell & Manella LLP in both the IPR and the litigation.